Hunting down cancer

Tumours continue bypassing cell pathways whilst molecular biologists doggedly try to understand how cancer works. Haren Rupani explains why we are still in our infancy of cancer knowledge.

“Cancer is much smarter than we are right now, it's a formidable enemy and we do not know all the tools that cancer has”
-Haren Rupani

Imaging techniques in the sphere of oncology has aided the monitoring of cancer and have developed in turn. As Haren Rupani, Global Head of Oncology Imaging at Novartis, explains, the way a cancer responds is traditionally evaluated by anatomic imaging, either by CAT scan, ultrasound or MRI. "This determines whether the tumour is present or not and whether it's shrinking, which has typically been what the FDA or the regulatory authorities have been allowing to do because there has been a long history. So these are time-proven methodologies of imaging techniques which the regulatory authorities allow for evaluation."

He explains how imagining has developed from anatomic, the more traditional method, due to a change in paradigm in terms of incorporation of functional imaging. "The modalities of functional imaging are those such as PET scanning and DCMRI. It enables us to look at how the tumour is behaving rather than if the is tumour present or not. Exploratory imaging from the regulatory perspective is not something that you can use for a primary endpoint; it can only be used for a secondary or exploratory endpoint, the reason being that these have not been validated as to reflect what the patient outcome is. That's the nature of exploratory imaging rather than traditional anatomical imaging," says Rupani.

Exploratory techniques

Novartis is endorsing such developments and Rupani cites a number of their benefits and the reasoning for the company's adoption of exploratory techniques. Traditionally it is used during the early phases to enable the physician to discern whether the trials are on track and how they may be working. Rupani notes the commonest reason, therefore, is for early response, as well as proof of concept and a proof of mechanism.

"The other area is to be able to evaluate an optimal biological dose rather than a maximum tolerated dose, so that is another very important function. You do not want to give medicine to a patient in excess of what is actually needed, you want to reduce the toxicity," he says. The other basic role, a very important role, is patient stratification. I've already mentioned basically tumour response, proof of concept, proof of mechanism, patient stratification, optimum biological dose versus maximum tolerated dose - these are the common indications to help us decide decisions.

"At Novartis 75 percent of the time we have conducted the early response. In approximately 10 percent of our trials we're also evaluating for optimal biological dose. The real goal for me and for Novartis, as well as the entire pharma industry, is getting the right medicine for the right patient in the right dose, and so that can be summarised as patient stratification. This is the ultimate goal, and imaging may not be the right tool for patient stratification because of the advantages and disadvantages of imaging.

"Biomarkers, can be divided into imaging and tissue biomarkers, so you take a blood sample, you take a biopsy of the tumour and you can conduct a lot of testing, and that's basically what tissue biomarkers are. So imaging and tissue biomarkers are all exploratory modalities that I use. We do not know which one is the most effective one and for what; only time will tell which, or both, of them will be useful patient stratification. The commonest reason why we use exploratory imaging is for early response to the drug."

Challenges

However, the rise of almost every pharma company to a multi-centre organisation conducting multi-regional trials poses its challenges for imaging. Rupani notes one as being standardisation and another as being visibility, being unable to locate the radio tracers that would be potentially done. He notes that 80 percent of exploratory imaging is with PET imaging, and the tracer is needed in order to deliver that. The final challenge is that of financial issues.

"Standardisation is very important," explains Rupani. "To give an analogy, if I have a weighing machine and you have a weighing machine and I have a 100 pound weight, that should measure 100 pounds on your weighing machine as well as mine. That's a very simplistic way of putting that. So when you're doing that at 50, 60, 70 trials, you cannot have the 100 pound being measured as 70, 80 or even 200 pounds. Standardisation is the most critical, and there are a lot of challenges that come in trying to standardise because you have different equipments, you have different ways of calibrating the machines, and that becomes a process. Standardisation remains number one.

"Number two, how do you deliver the radio tracer? Radio tracers always have their half life, so different radio tracers have different half lives; the shorter the half life the more difficult it becomes to deliver that to the various sites. Also, what if it is not FDA or regulatory approved, like an EMEA in Europe, then before you can inject that into a human you need an investigation, a new drug application, which is a labourious, long process. So the practicality and feasibility of doing studies with radio tracers, which has not been approved for human use has its own challenges.

"The last factor is cost. These are not cheap things to do so it's important to know what you are getting out of that. Typically exploratory imaging using PET scanning is always done in a subset of people; you cannot obviously do it in all the patient population because of the cost factor," he explains.

Rupani adds that keeping the cost in check is attributable to efficiency - the right patient, the right medicine, the right dose. He notes imaging to not only be expensive, but also time-consuming: before the regulatory authorities approve surrogate markers, allowing Rupani and his team to replace and evaluate them, the validation process first takes a long time to process. "This is such a huge task to overcome that there's no single person or single entity, be it the government, manufacturers or the industry, that can have the expertise and the resources to do this alone. It has to be a pooled thing," he says.

"However, society as a whole cannot afford not to do it. Unfortunately all of us will either have cancer or heart disease, one of the two, and from a patient point of view you want to look at that. Everybody will become a patient one day. This is something that we cannot afford not to do, so as a society it becomes important to know what are our priorities are. Do we want to spend money in research and development or not? 

"On an individual basis for pharma, there are different approaches. There are companies who do invest and there are companies that do not invest, so I'm blessed at Novartis that there is a lot of importance given and we are investing this. This is going to be long, it is going be expensive, and it's going to be often frustrating, but Novartis has got the long-term view in terms of investing into this technology. I'm hoping that at a government level there has also increased interest and investment into research and development so that cost does not become an issue; it's a question of priorities. It all depends what we want to spend our money on."

Discovery difficulties

Understanding cancer drug discovery is not easy, irrespective of financial challenges. Rupani joined the pharma industry with a background in radiology and nuclear medicine, having to learn molecular biology during his entry. "The thing that fascinates me, each and all of us, is that we have 100 trillion cells in our body. When we look under the microscope and see the way the cell functions, we cannot understand it - there are more than 100 different cell pathways. Although now the medications are based upon targeting a cell pathway, we attack one of the 100 pathways that are occurring and we know that sometimes multiple therapies work better than just one therapy because now we are targeting two or three pathways.

"Our knowledge of that is in its infancy, and depending upon how the tumour develops cancer figures out a way of bypassing these pathways. It figures out the ways of becoming not responsive to what you're giving, so we are at our infancy in our knowledge of molecular biology, how cancer works. Cancer is much smarter than we are right now, it's a formidable enemy and we do not know all the tools that cancer has, which is the reason why our understanding is still in its infancy and until we make progress in this it's going be a long battle," he concludes.

Haren Rupani is the Global Head of Oncology Imaging at Novartis.